All ionotropic glutamate receptors share the same domain structure with two extracellular domains; the amino terminal domain (ATD) and ligand binding domain (LBD), a transmembrane domain (TM) and a cytoplasmic carboxy terminal domain (CTD). The synaptic trafficking of glutamate receptors is of fundamental importance for synapse development and plasticity. Virtually all the work on this topic has focused on the CTD of the various subclasses of glutamate receptor. These studies, while contributing importantly to our understanding, left many unanswered question. On the other hand virtually nothing is known about the role of the ATDs of these receptors, which account for approximately 50% of the protein. Our recent results have established a critical role of the ATD for the subunit specific synaptic trafficking, not only for AMPA receptors, but also for kainate receptors and for the Delta1 glutamate receptor. The overall goals of this project is to 1) determine the functional similarities and differences of the ATDs of subunits within a class of glutamate receptor as well as between different classes of receptor and 2) identify synaptic cleft proteins that specifically interact with the extracellular domains of the various glutamate receptors. To accomplish these objectives the first approach will be to carry out a series of deletions of the ATD to determine what regions are necessary for their function. Based on the regions we identify, we will carry out a series of domain swapping experiments to determine if the regions we identify are sufficient for their function. The second approach will focus on identifying synaptic cleft proteins that interact with the extracellular domains of the glutamate receptors. This will rely on both a candidate approach and an unbiased proteomic approach. Specifically, we will 1) determine the role of the ATD in subtype- and subunit-specific ionotropic glutamate receptors in constitutive and plasticity-dependent synaptic targeting; 2) determine the role of GluD1 in excitatory synaptic transmission 3) characterize MDGA Proteins as novel ATD binding proteins These results will provide basic information about the rules and proteins involved in the extracellular control of basal and activity-dependent synaptic glutamate receptor trafficking.